Mitochondria, distinguished by their unique structural and functional attributes, play a substantial role in the pathology of numerous diseases, encompassing cancer, diabetes, cardiovascular disorders, and age-related neurodegenerative diseases. Grounded on the notion that the modulation of mitochondrial activity could harbor significant therapeutic potential, this study navigates through this innovative approach. The study further accentuates the promising role of mitochondrial proteins (MPs) as therapeutic targets, brought into the spotlight by recent advancements in the field. With 312 of the roughly estimated 1500 mitochondrial proteomes known to interact with small compounds, these MPs become conspicuous candidates for drug targeting. However, the current clinical trial landscape unveils a scarcity of drugs specifically targeting MPs, despite these interactions' involvement in a multitude of biological processes. The study acknowledges the recent surge in the number of identified proteins localizing to the mitochondria and the accessible MP 3D structures, paving the way for unparalleled experimental screening and in silico prediction of mitochondrial drug targets. It underscores the potential of mitochondrial drug targeting techniques and innovative mitochondrial targets with a view to shaping future mitochondrial-directed therapies. Embodying a novel, comprehensive methodology to mitochondrial therapeutics, the study not only delves into the underpinning mechanisms of mitochondrial dysfunction but also investigates the prospects of new drug-targeting techniques and potential mitochondrial targets. The integration of genetic, proteomic, and chemogenomic techniques provides a multifaceted approach to mitochondrial drug discovery. The pioneering strategy of administering biologically active compounds directly into the mitochondria of living cells could revolutionize our approach to disease treatment and prevention. The prospect of directing biologically active compounds to the mitochondria of living cells could potentially lead to new strategies for manipulating mitochondrial functionality and selectively safeguarding or exterminating cells, achieving therapeutic benefits in a host of disorders.